base excision repair

The multi-functional cyclin-dependent kinase (CDK) inhibitor, p21 plays a diverse role in regulating the DNA damage response, senescence, DNA repair, transcription and apoptosis. p21, also known as p21WAF1/Cip1 or CDKN1A, belongs to the CIP/Kip family of CDK inhibitors.

In normal cells, p21 functions as a cell cycle inhibitor and anti-proliferative effector. Upon DNA damage and genotoxic stress, the tumour suppressor p53 is activated and induces the expression of p21. p21 can bind to cyclin A/CDK2, E/CDK2, D1/CDK4 and D2/CDK4 complexes and suppress their catalytic activity. This prevents the phosphorylation of Retinoblastoma protein (Rb) and leads to the arrest in G1/S cell cycle progression and G2/M transitions. In addition, p21 also inactivates Rb by mediating its degradation. Studies also show that p21 can mediate cellular senescence via p53-dependent and p53-independent pathways.

p21 can also acts as either an enhancer or a suppressor of various DNA repair pathways. In DNA damaged cells, p21 is recruited to damaged sites and co-localises with double strand break (DSB) repair proteins to facilitate various repair pathways. p21 has been implicated in nucleotide excision repair (NER), base excision repair (BER) and DNA translesion synthesis (TLS) by disrupting the proliferating cell nuclear antigen (PCNA) interaction with other DNA repair factors and promoting PCNA degradation. PCNA-dependent DNA replication is also inhibited by p21. Another important function of p21 is regulating the transcription of genes involved in various biological process such as cell cycle progression, DNA repair and regulation of apoptosis, such as E2F family, NF-κB, c-myc, STAT and p300/CPB.

In response to DNA damage and stress signals, p21 has been shown to exert anti-apoptotic activity. The cytoplasmic interaction of p21 with pro-caspase 3 and caspase 2 prevents their activation of apoptosis. Fas-induced apoptosis is also inhibited via p21 interaction with caspase 3 and inhibition of its activity. p21 also forms a complex with stress induced kinases, such as apoptosis signal regulating kinase 1 (ASK1) to inhibit apoptosis. In addition, the phosphorylation of p21 by Akt1/PKB enhances its stability and promotes cell survival.